Systematic and state-of the science review of the role of environmental factors in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease

The etiology of sporadic amyotrophic lateral sclerosis (ALS) is still unclear. We evaluate environmental factors suspected to be associated with ALS for their potential linkage to disease causality and to model geographic distributions of susceptible populations and expected cases worldwide. A PRISMA systematic literature review was performed 2021. Bradford Hill criteria were used to identify and rank environmental factors and a secondary review of ALS diagnoses in population studies and ALS case or cohort studies was conducted. Prevalence rate projection informed estimates of impacted regions and populations. Among 1710 papers identified, 258 met the inclusion criteria, of which 173 responded to at least one of nine Bradford Hill criteria among 83 literature-identified ALS environmental factors. Environmental determinants of ALS in order of decreasing significance were β-N-methylamino-L-alanine (BMAA), formaldehyde, selenium, and heavy metals including manganese, mercury, zinc, and copper. Murine animal models were the most common methodology for exploring environmental factors. Another line of investigation of 62 population exposure studies implicated the same group of environmental agents (mean odds ratios): BMAA (2.32), formaldehyde (1.54), heavy metals (2.99), manganese (3.85), mercury (2.74), and zinc (2.78). An age-adjusted incidence model estimated current total ALS cases globally at ~85,000 people compared to only ~1600 cases projected from the reported ALS incidence in the literature. Modeling with the prevalence microscope equation forecasted an increase in U.S. ALS cases from 16,707 confirmed in 2015 to ~22,650 projected for 2040. Two orthogonal methods employed implicate BMAA, formaldehyde, manganese, mercury, and zinc as environmental factors with strong ALS associations. ALS cases likely are significantly underreported globally, and high vulnerability exists in regions with large aging populations. Recent studies on other diseases with environmental determinants suggest the need to consider additional potential triggers and mechanisms, including exposures to microbial agents and epigenetic modifications.